Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same

ABSTRACT

The invention concerns an oral galenic form for prolonged release of anti-hyperglycaemic (metformin) active principles. Said medicine enables to obtain an efficient therapeutic protection over 24 hours by overcoming the problems of bypass of the absorption window and the massive localised release of active principles. Therefor, said medicine comprises several thousand anti-hyperglycaemic (metformin) microcapsules each consisting of a core comprising at least an anti-hyperglycaemic agent and of a coating film applied on the core and enabling the prolonged release in vivo of the anti-hyperglycaemic agent. Said microcapsules have a grain size distribution ranging between 50 and 100 microns. The reproducibility of the transit kinetics and hence of bioavailability are very high. There results for the patient a lesser risk of hyperglycaemic or hypoglycaemic. The invention also concerns the preparation of said medicine and the use of a plurality of said microcapsules for making an anti-hyperglycaemic medicine. The invention is applicable to the treatment of type II diabetes.

This application is a U.S. National Stage of International applicationPCT/FR01/03625, filed on Nov. 19, 2001.

The field of the present invention is that of oral pharmaceutical dosageforms which make possible the prolonged release of antihyperglycemicactive principles. More specifically, the present invention relates to anovel medicament which can be administered by the oral route and whichmakes possible the prolonged release in vivo of a biguanide, such asmetformin or buformin, or any pharmaceutically acceptable salt of thesecompounds, such as, for example, metformin hydrochloride.

The term “prolonged-release oral pharmaceutical dosage forms” isunderstood to mean the oral pharmaceutical dosage forms which makepossible a slowed release of active principles in comparison with theconventional pharmaceutical dosage forms administered according to thesame route. This definition is that given by the European Agency for theEvaluation of Medicinal Products in its Note on the Quality of ModifiedRelease Products of 29 Jul. 1999.

This definition excludes delayed-release oral pharmaceutical dosageforms, which consist of pharmaceutical dosage forms which make itpossible to delay the release of the active principles for apredetermined period of time after administration, this release,equivalent to that of the conventional pharmaceutical dosage forms, thenresulting from a time lag without modification of the otherpharmacokinetic parameters (Note on the Quality of Modified ReleaseProducts of 29 Jul. 1999, European Agency for the Evaluation ofMedicinal Products).

The prior art comprises numerous technical proposals for producingprolonged-release forms of pharmaceutical products with the aim ofextending the duration of the therapeutic coverage and of improving thecomfort of the patients and the probability of them observing thedosage. However, very few studies have been devoted to developingcontrolled-release antihyperglycemic forms.

These antihyperglycemics, and in particular metformin hydrochloride,exhibits a low intrinsic permeability in the distal parts of thegastrointestinal tract. Its absorption therefore takes place essentiallyin the upper part of the gastrointestinal tract. Its oralbioavailability is of the order of 40 to 60%. It decreases when the doseincreases, which suggests a saturable absorption or an absorptionlimited by the permeability and the transit time. Products exhibiting anabsorption limited to the upper part of the gastrointestinal tract,which are said to “have an absorption window”, are regarded as poorcandidates for prolonged-release oral forms. The administration of theseproducts by a conventional prolonged-release system can actually bereflected by plasma concentrations below the therapeutic threshold andthus with an ineffective treatment.

Another characteristic of these antihyperglycemics, such as metforminhydrochloride, is their very high solubility in water: more than 300 g/lat 25° C. This presents problems when it is a question of obtaining aformulation exhibiting a low and fully controlled rate of release,without sudden discharge (burst effect). To overcome this, it isgenerally necessary to use large amounts of polymers to form a matrix ora barrier capable of sufficiently slowing down the release of themetformin to produce the desired plasma concentration profile and, inthis case, the formulator has every interest in favoring the monolithicforms, which offer less surface area to the diffusion of the activeprinciple.

Furthermore, the daily dose of active principle can be of the order ofone gram. This is the case in particular for metformin. The result ofthis is that the prolonged-release forms of metformin, inter alia, canbe of large size. Such a large monolithic unit form can undergo randomgastric emptying and can therefore remain for a poorly controlled timeupstream of its absorption window. This results in a random and poorlycontrolled, in amount and duration, absorption of the active principle.Frequent disappointments (bypass) of this type have the consequence, inthe case of antihyperglycemics, that glycemia may not be correctlycontrolled, which can have extremely harmful consequences for thediabetic patient.

The large monolithic pharmaceutical dosage form may also be foundblocked in the twists and turns of the gastrointestinal tract. A massiveand highly localized release of the active principle then occurs (dosedumping), which active principle not only will not be absorbed accordingto the desired profile but, moreover, is capable of causing localinjuries to the tissues at the spot of the massive release.

Thus, the prior art only discloses monolithic forms capable of remainingfor a certain time in the stomach (gastroretention), so as to releasethe metformin upstream of its absorption window.

Patent application WO 98/55107 discloses tablets comprising a matrixformed of hydrophilic polymer of high molecular weight (polyoxyethylene)comprising metformin. Once ingested, this matrix swells to largedimensions (e.g. 7.2 mm in diameter×8.8 mm in length), promoting itsretention by the stomach, while limiting the rate of dissolution of themetformin.

Patent WO 99/47125 discloses a controlled-release monolithic tabletformed:

-   -   of a core comprising:        -   the antihyperglycemic active principle (metformin),        -   a water-insoluble binding agent (polyvinylpyrrolidone),        -   an absorption promoter (bile salt),    -   and of a semipermeable membrane (insoluble cellulose derivative)        coating the core and pierced by at least one hole.

Conventionally, in techniques for the manufacture of tablets, thetablets according to WO 99/47125 are obtained from uncoated granules,prepared by wet granulation, that is to say agglomeration of metforminparticles using the abovementioned binding agent. The granules have asize significantly greater than that of the starting metforminparticles.

This pharmaceutical dosage form is supposed to have a therapeuticcoverage over 24 hours after oral administration on a full stomach.

One of the disadvantages of this pharmaceutical dosage form is thepresence of this absorption promoter, which can weaken the intestinalwall and can, over prolonged administration, have undesirable sideeffects.

Another disadvantage is that this “tablet” form has a variable gastricresidence time, unlike a microparticle pharmaceutical dosage form, theresidence time of which is kept in balance by the large number ofparticles.

Patent WO 99/47128 discloses a prolonged-release oral pharmaceuticaldosage form which makes possible prolonged residence in the stomach.

It is a form suitable for active principles possessing high solubilityin water and exhibiting an absorption window limited to the top part ofthe gastrointestinal tract (metformin). This is a two-phase system andcomprises:

-   -   a particulate internal phase formed of individual granules        charged with AP. The distinctive feature of these granules is        that they are uncoated and comprise one or more excipients which        can be:        -   a hydrophobic polymer: copolymer of (meth)acrylic acid            (Eudragit®), ethylcellulose,        -   and/or a hydrophilic polymer: sodium carboxymethylcellulose            or sodium alginate,        -   and/or other hydrophobic compounds: waxes, fatty alcohols,            fatty acid esters,    -    and an external solid continuous phase in which the particles        of the internal phase are embedded, this external continuous        solid phase comprising:        -   one or more hydrophilic polymers:            [hydroxypropylmethylcellulose—HPMC—(with a viscosity of 5            cPs and 1×10⁵ cPs), microcrystalline cellulose],        -   and/or one or more hydrophobic polymers,        -   and/or one or more other hydrophobic compounds (waxes, fatty            alcohols, fatty acid esters).

This pharmaceutical dosage system is preferably in the form of oblongtablets. It is presented as having an increased residence time in thetop part of the gastrointestinal tract (stomach/small intestine) by aneffect of increase in size, without, however, achieving an upper limitresulting in blockage.

One disadvantage of this pharmaceutical dosage form is that it exhibitsa variable gastric residence time, unlike a microparticle pharmaceuticaldosage form, the residence time of which is kept in balance by the largenumber of particles.

Furthermore, it is probable that this pharmaceutical dosage systemaccording to WO 99/47128 (preferably a tablet) has a low mechanicalstrength in a gastric environment. In such an event, the release of theAP would no longer be controlled.

These three inventions refer to large monolithic forms which have to beingested as such. Thus:

-   -   for a dose of 1 g of metformin: patent WO 98/55107 provides 8        tablets 10.4×6.6 mm present in 4 gelatin capsules;    -   for a dose of 1 g of metformin: patent WO 99/47128 provides 2        large oblong tablets;    -   for a dose of 850 mg of metformin: patent WO 99/47125 provides a        tablet with a diameter of 12 mm.

Problems of observance may be encountered with these forms for patientshaving difficulties in swallowing.

Furthermore, the plasma concentration profile obtained from thesesystems is highly conditioned by the residence time in the stomach,which can be the subject of large interindividual variations. Themonolithic systems are subject to and sometimes accentuate the effect ofthese interindividual variations, which can result in the treatmentbeing ineffective in a not insignificant portion of the populationtreated.

Finally, these pharmaceutical dosage systems are capable of resultingeither in problems of bypass of the absorption window or in problems oflocalized accumulation of the active principle, and of subsequentinjuries.

PCT Application WO 96/11675 discloses medicinal and/or nutritionalmicrocapsules for the administration per os of active principle, withthe exception of aspirin and without any details of a specific class ofactive principles, namely antihyperglycemics and in particularmetformin. These medicinal microcapsules are composed of particles ofactive principle (without antihyperglycemics being specified), eachcovered with a coating film comprising at least one film-forming polymerP1, at least one nitrogenous polymer P2, at least one plasticizer and atleast one surfactant and/or lubricant. The medicinal microcapsulesaccording to WO 96/11675 do not solve the specific problem of thetherapeutic coverage over 24 hours of antihyperglycemics and with anabsorption window in the top parts of the gastrointestinal tract, whichare very soluble in water and which have to be ingested at high doseseach time they are taken (1 g per day).

The document WO 00/28989 discloses delayed-release compositions whichare provided in the form of gelatin capsules comprising multiple coresof granules comprising an insulin sensitization agent and anotherantidiabetic agent, which can be a biguanide, such as metformin. Thecores of granules can be coated with an enteric composition and inparticular a composition composed of a film-forming polymer, such asEudragit L100-55. However, this document does not disclose anantihyperglycemic medicament which can be administered per os, which isprovided in the form of microparticles which make possible the prolongedrelease of the antihyperglycemic active principle or principles.

In such a state of the art, one of the essential objectives of thepresent invention is to provide a novel pharmaceutical dosage system forthe oral administration of antihyperglycemic active principles, thissystem having to make it possible to obtain an effective therapeuticcoverage over 24 hours while overcoming the problems of bypass of theabsorption window and of massive localized release of active principle.

One objective of the present invention is to provide a pharmaceuticalform composed of a large number, of the order of several thousand, ofantihyperglycemic microcapsules and in particular metforminmicrocapsules, this multiplicity of microcapsules statisticallyproviding good reproducibility of the kinetics of transit of theantihyperglycemic (metformin) throughout the gastrointestinal tract.This results in better control of the bioavailability and thus, for thepatient, in a reduced risk of hyperglycemia or of hypoglycemia.

One objective of the present invention is to provide a prolonged-releaseantihyperglycemic, and in particular metformin, multimicrocapsulepharmaceutical dosage form, this pharmaceutical dosage form beingcomposed of a tablet which is dispersible in a liquid or in the mouth,of an effervescent tablet or of powder in sachets.

Another objective of the present invention is to provide aprolonged-release antihyperglycemic, and in particular metformin,multimicrocapsule form which results, after oral administration, in aplasma peak after more than 6 hours approximately.

Another objective of the present invention is to provide aprolonged-release antihyperglycemic, and in particular metformin,multimicrocapsule form, the bioavailability of this not being reduced byadministration on a full stomach.

Another objective of the present invention is to provide aprolonged-release antihyperglycemic, and in particular metformin,multimicrocapsule form which provides sufficient therapeutic coveragefor administration of the active principle once or twice daily.

Another object of the present invention is to obtain a multimicrocapsulesystem which provides for the in vitro release of the antihyperglycemicproducts over more than 8 hours while avoiding the use of large amountsof polymers, the active principle content remaining comparable to,indeed even greater than, that of monolithic forms.

Another object of the present invention is to provide a simple andeconomic process for the preparation of the abovementionedmultimicrocapsule pharmaceutical dosage form.

The objectives stated above, among others, are obtained by theinvention, which provides, first, a medicament based on at least oneantihyperglycemic which can be administered by the oral route,characterized:

-   -   in that it comprises a plurality of microcapsules each composed        of a core comprising at least one antihyperglycemic and of a        coating film applied to the core and which makes possible the        prolonged release in vivo of the antihyperglycemic(s),        with the exclusion of the coating films composed of enteric        compositions and of the coating films with the composition        following:

-   1—at least one film-forming polymer (P1) which is insoluble in the    fluids of the tract, present in a proportion of 50 to 90%,    preferably 50 to 80%, by weight on a dry basis with respect to the    total mass of the coating composition and composed of at least one    water-insoluble cellulose derivative of cellulose, namely    ethylcellulose and/or cellulose acetate;

-   2—at least one nitrogenous polymer (P2), present in a proportion of    2 to 25%, preferably 5 to 15%, by weight on a dry basis with respect    to the total mass of the coating composition and composed of at    least one polyacrylamide and/or one poly-N-vinylamide and/or one    poly-N-vinyllactam, namely polyacrylamide and/or    polyvinylpyrrolidone;

-   3—at least one plasticizer, present in a proportion of 2 to 20%,    preferably of 4 to 15%, by weight on a dry basis with respect to the    total mass of the coating composition and composed of at least one    of the following compounds: glycerol esters, phthalates, citrates,    sebacates, esters of cetyl alcohol, castor oil, salicylic acid and    cutin;

-   4—and optionally at least one surface-active and/or lubricating    agent, present in a proportion of 2 to 20%, preferably of 4 to 15%,    by weight on a dry basis with respect to the total mass of the    coating composition and chosen from anionic surfactants, namely    alkali metal or alkaline earth metal salts of fatty acids, stearic    acid and/or oleic acid being preferred, and/or from nonionic    surfactants, namely polyoxyethylenated sorbitan esters and/or    polyoxyethylenated castor oil derivatives, and/or from lubricating    agents, such as calcium stearate, magnesium stearate, aluminum    stearate or zinc stearate, or such as sodium stearylfumarate and/or    glycerol behenate; it being possible for said agent to comprise just    one or a mixture of abovesaid products;    -   in that these microcapsules have a particle size of between 50        and 1000 microns, preferably between 100 and 750 microns and        more preferably still between 200 and 500 microns.

The term “enteric compositions” is understood to mean the compositionswhich confer on the coating a resistance to acidic pH (gastric pH) andwhich make possible release of the active principle or principles whenthe pH is raised.

Thus, the medicament according to the invention is particularly suitablefor antihyperglycemic active principles which have the characteristic ofhaving an absorption window situated in the top parts of thegastrointestinal tract (stomach and start of the small intestine), whichare very soluble in water and for which the dosage is of the order of 1g per day, which requires the ingestion of a large amount of producteach time it is taken.

This medicament, in a “multimicrocapsule” pharmaceutical dosage formcomposed of a plurality of microcapsules, necessarily restricts, forstatistical reasons, the risk of bypass of the absorption window andeliminates the risk of localized accumulation of active principle. Thisresults in an optimum absorption of antihyperglycemics in the absorptionwindow, in an amount such that and over a time such that the therapeuticcoverage can be guaranteed over at least 12 h with all the therapeuticsafety desirable (control of glycemia). This is because the large numberof particles (e.g. of the order of 10 000) makes possible a reproducibledistribution, thus reducing the risks of hyper- and hypoglycemia.

The antihyperglycemics more particularly affected by the invention arethose chosen within the group consisting of metformin and its salts,such as metformin hydrochloride.

The appended FIGS. 1 and 2 are photographs (respectively before andafter a dissolution test, cf. examples below) on several constituentmicrocapsules of the medicament according to the invention. These photosclearly show that each individual microcapsule comprises a core wrappedin a coating film which controls the prolonged release of theantihyperglycemic active principle or principles.

The size of each microcapsule is less than 1 mm and in practice between200 and 500 μm, as is apparent in the photo of FIG. 1. It should beemphasized that this is not a matter of an agglomerate of particles ofantihyperglycemics in granules with a size of greater than 1 mm and forwhich the matrix is formed by a polymer binder.

The medicament according to the invention relates to dry pulverulentforms or forms in suspension in a liquid or alternatively formsdisintegrated in the mouth or in a liquid.

In fact, the medicament according to the invention can be categorized asa novel “multimicrocapsule” pharmaceutical dosage system intended to beeasy to administer per os and which makes possible prolonged release invivo, guaranteeing therapeutic coverage of at least 12 hours and,preferably, over at least 24 hours.

The size and the coating of the microcapsules are preferably chosen sothat, everything else otherwise being equal, its bioavailability duringoral administration on a full stomach is at least equal to itsbioavailability during oral administration on an empty stomach.

According to a preferred characteristic of the invention, the coatingfilm for the microcapsules is designed so that, after ingestion of agiven dose of antihyperglycemic, the time (Tmax) corresponding to themaximum plasma concentration in the curve of the plasma concentration asa function of time is greater than or equal to 6 hours, and thebioavailability, given by the area under the curve (AUC), is greaterthan or equal to 60%, preferably 80%, with respect to that obtained withthe same dose of immediate-release antihyperglycemic.

Curves of this type, which give the plasma concentration as a functionof time elapsed after ingestion, describe the therapeutic coverage andthe therapeutic effectiveness of the medicament. There are grounds forrecording that they are entirely satisfactory for the multimicrocapsuleand antihyperglycemic medicament according to the invention.

Thus, the medicament according to the invention offers entirelyadvantageous prospects in the treatment of type II diabetes, alone or incombination with other antidiabetic medicaments, such as insulin.

In an entirely surprising and unexpected way, the oral multimicrocapsulepharmaceutical dosage system according to the invention does not requirethe use of large amounts of excipient polymers in relation to the massof antihyperglycemics. Contrary to the situation for knownpharmaceutical dosage systems of monolithic type with large dimensions.

Thus, according to an advantageous provision of the invention, the meanfraction by mass of antihyperglycemic in the microcapsules is greaterthan 50%, preferably greater than or equal to 60%.

The technical problems solved by the invention are more specificallythose encountered for antihyperglycemics and in particular those chosenfrom biguanides, preferably from the group of biguanides comprisingmetformin and buformin and their salts, metformin and its salts beingparticularly preferred.

The medicament according to the invention can also be defined bycharacteristics of in vitro release of the antihyperglycemic(s), bydissolution in an aqueous medium of the coating film. From which itresults that, in an in vitro dissolution test known as the type IIdissolutest in accordance with the Pharmacopoeia, the dissolution of theantihyperglycemic extends over at least 8 hours, preferably at least 20hours.

The multimicrocapsule medicament according to the invention can exist invarious pharmaceutical dosage forms, including in particular:

-   -   tablets which can disintegrate in the mouth,    -   tablets which can disintegrate by effervescence in a liquid        (water),    -   tablets which can disintegrate in a liquid (water),    -   powders of given doses packaged in sachets,    -   suspensions of microcapsules in a liquid (water),    -   gelatin capsules comprising a powder formed of microcapsules.

According to a specific but nonlimiting embodiment of the invention, themultimicrocapsule medicament is composed of a pharmaceutical dosageform, the dose of antihyperglycemic of which is between 800 and 1200 mg,preferably between 900 and 1100 mg and more preferably still of theorder of 1000 mg.

Such a dose is particularly suitable for the treatment of type IIdiabetes, according to an effective dosage which makes it possible tocontribute to maintaining glycemia at acceptable levels 24 hours afterthe medicament has been taken.

This multimicrocapsule medicament, the antihyperglycemic dose of whichis between 800 and 1200 mg, preferably between 900 and 1100 mg and morepreferably still of the order of 1000 mg, is advantageously composed ofseveral thousand microcapsules as defined above, this multiplicityproviding good reproducibility of the gastrointestinal transit of theantihyperglycemic, thus reducing the risk to the patient of hypo- orhyperglycemia.

To give a few details of the structure of the microcapsules, it isspecified that the core of said microcapsules can be, for example, agranule comprising antihyperglycemic and granulation excipients and/or aparticle of antihyperglycemic, preferably a monocrystal.

In the core of the microcapsules, the antihyperglycemic can be used incombination with one or more excipients. This is in particular the casewhen the core is composed of a granule. The excipients then employed arethose which are conventional in granulation.

In practice, the film coating deposit on each granule can be composed ofone or more film-forming macromolecules well known to a person skilledin the art for preparing prolonged-release forms. For example, andwithout the list being exhaustive, it can be chosen from the followingfamilies: cellulose ethers, cellulose ethers/esters, cellulose esters,cellulose diesters, cellulose triesters, cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose diacetate and triacetate,cellulose acetate/propionate, cellulose acetate/butyrate,polymethacrylates, waxes and vinyl acetate copolymers.

Preferably, the film-forming macromolecule is ethylcellulose, Eudragit®RS, Eudragit® RL or cellulose acetate.

More preferably still, use will be made of the combinations of cellulosederivatives and of at least one pharmaceutically acceptable hydrophilicpolymer.

The fraction by mass of cellulose derivatives is advantageously between30 and 90% and more advantageously still between 50 and 80%.

The film coating can also comprise the excipients commonly used asplasticizers. They can be chosen from the following nonexhaustive list:tributyl acetylcitrate, triethyl acetylcitrate, acetylated glycerides,castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate,dibutyl sebacate, dimethyl phthalate, glycerol, glycerol monostearate,glyceryl triacetate, polyethylene glycol,polyoxyethylene/polyoxypropylene copolymers, propylene glycol, tributylcitrate, triethyl citrate, adipate, azelate, enzoate, citrate, citricacid esters, triacetin, vegetable oils, glycerin sorbitol, diethyloxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate or glycerol tributyrate.

Other commonly used excipients can be introduced into the coating, suchas soluble or insoluble fillers (talc, inorganic salts, sugars,polyvinylpyrrolidone, polyethylene glycol, and the like), lubricants,dyes or pigments.

According to another of its aspects, the invention is targeted at theprocess for the preparation of the medicament as defined above.

This process consists:

-   -   in employing granules comprising antihyperglycemic(s) and        granulation excipients or alternatively particles of        substantially pure antihyperglycemic(s), preferably monocrystals        of antihyperglycemic(s);    -   and in then spraying, over these granules and/or these        particles, a coating solution comprising one or more products        selected from the group consisting of:        -   film-forming macromolecules, preferably chosen from the            group consisting of:            -   cellulose ethers, cellulose ethers/esters, cellulose                esters, cellulose diesters, cellulose triesters,                cellulose acylate, cellulose diacylate, cellulose                triacylate, cellulose diacetate and triacetate,                cellulose acetate/propionate, cellulose                acetate/butyrate, polymethacrylates, waxes and vinyl                acetate copolymers;        -    ethylcellulose, Eudragit® RS, Eudragit® RL and cellulose            acetate being particularly preferred;        -   plasticizers, preferably chosen from the following            nonexhaustive list: tributyl acetylcitrate, triethyl            acetylcitrate, acetylated glycerides, castor oil, dibutyl            phthalate, diethyl phthalate, diethyl sebacate, dibutyl            sebacate, dimethyl phthalate, glycerol, glycerol            monostearate, glyceryl triacetate, polyethylene glycol,            polyoxyethylene/polyoxypropylene copolymers, propylene            glycol, tributyl citrate, triethyl citrate, adipate,            azelate, enzoate, citrate, citric acid esters, triacetin,            vegetable oils, glycerin sorbitol, diethyl oxalate, diethyl            malate, diethyl fumarate, dibutyl succinate, diethyl            malonate, dioctyl phthalate or glycerol tributyrate;        -   and optionally other excipients selected from soluble or            insoluble fillers (talc, inorganic salts, sugars,            polyvinylpyrrolidone, polyethylene glycol, and the like),            lubricants, dyes or pigments;            using a technology provided for this purpose and known to a            person skilled in the art, such as that involving a Wurster®            system from Glatt or a Precisiocoater® system from            Aeromatic.

As already indicated above, the granules capable of forming the core ofthe microcapsules are obtained by conventional granulation techniques.

The granulation excipients employed are well known to a person skilledin the art and are in particular those exemplified above.

The innovative characteristics of the process result from the materialsemployed and from the combination of the carefully selected physicalparameters.

In accordance with the invention, provision is also made, as solution tothe problems mentioned at the beginning of the present account, namely:bypass of the absorption window, massive and localized release of theantihyperglycemic, pharmaceutical dosage form which can be easilyswallowed, everything from the viewpoint of effective and certaintherapeutic coverage for at least 12 h (control of glycemia), to use aplurality of microcapsules:

-   -   each composed of a core comprising at least one        antihyperglycemic and of a coating film applied to the core and        which makes possible the prolonged release in vivo of the        antihyperglycemic(s),    -   and having a particle size of between 50 and 1000 microns,        preferably between 100 and 750 microns and more preferably still        between 200 and 500 microns;        for manufacturing a medicament based on at least one        antihyperglycemic which can be administered by the oral route,        which can be easily swallowed and which contributes to the        control of glycemia (reduction in the risk of hypo- or        hyperglycemia) over at least 12 h in a reliable manner, while        limiting problems of bypass, of accumulation and of localized        and massive release of antihyperglycemic.

According to yet another of its subject matters, the present inventionrelates to a method for the treatment of type II diabetes, in whichrecourse is had to a medicament as defined above as product per se or asproduct obtained by the process described above.

The examples which follow will make possible a better understanding ofthe invention and an apprehension of all these advantages and all itsalternative embodiments.

EXAMPLES

Description of the Figures

FIGS. 1 and 2 are photographs of microcapsules respectively before andafter the dissolutest dissolution test employed and defined in theexamples.

FIG. 3 is a curve giving the percentage of dissolution (dissolutest) asa function of time of metformin microcapsules according to example 1.

FIG. 4 is a curve giving the percentage of dissolution (dissolutest) asa function of time of metformin microcapsules according to example 2.

EXAMPLE 1

159.5 g of stearic acid and 159.5 g of ethylcellulose are dissolved in2870 g of isopropanol maintained at 50° C. This solution is sprayed over700 g of metformin.HCl crystals with a mean diameter of between 100 and200 μm charged to a Glatt GPCG1 spray coater. The film-coatingconditions are: product temperature: 38-42° C., rate of spraying: 10g/min, atomization pressure: 2 bar.

The microcapsules obtained were tested in a type II dissolutest inaccordance with the Pharmacopoeia in a KH₂PO₄/NaOH buffer medium at pH6.8, maintained at 37° C. and stirred at 10 revolutions/min.

It turns out that the microcapsules were not modified externally by thedissolution test. This proves that they indeed comprise a coatingthrough which the metformin diffused during the dissolution test andwhich was not affected by the dissolution.

The dissolution profile obtained is as follows:

TABLE 1 Time Metformin dissolved (hour) (%) 2 14.7 4 34.4 8 69.4 12 87.516 94.3 20 97.1

The dissolution profile of the product prepared in this example isrepresented in FIG. 3.

EXAMPLE 2

51.13 g of ethylcellulose and 5.73 g of castor oil are dissolved in amixture of 393 g of acetone and 262 g of isopropanol. This solution issprayed over 200 g of metformin.HCl crystals with a mean diameter ofbetween 200 and 500 μm charged to a Niro CC1 spray coater. Thefilm-coating conditions are: product temperature: 38-42° C., rate ofspraying: 4 g/min, atomization pressure: 1 bar.

The microcapsules obtained were tested in a type II dissolutest inaccordance with the Pharmacopoeia in a KH₂PO₄/NaOH buffer medium at pH6.8, maintained at 37° C. and stirred at 10 revolutions/min.

The dissolution profile obtained is as follows:

TABLE 2 Time Metformin dissolved (hour) (%) 2 29.4 4 56.0 8 85.2 12 93.616 96.9 20 98.7

The dissolution profile of the product prepared in this example isrepresented in FIG. 4.

EXAMPLE 3

Two gelatin capsules with a size of 00, each comprising 500 mg of coatedmetformin in the microcapsules described in example 2, or else 4Glucophage tablets, each comprising 250 mg of metformin, areadministered to 12 healthy subjects after eating with 250 ml.

Blood samples are taken at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20,24 and 36 hours after administration in order to analyze the metforminconcentration.

The mean plasma concentration profile demonstrates an increase in thetime corresponding to the plasma concentration maximum, this beingachieved without a very significant decrease in the bioavailabilityevaluated by the area under the plasma concentration profile between thepoints and 36 hours.

The main pharmacokinetic parameters are listed in table 3 below.

TABLE 3 Relative Tmax Cmax AUC 0–36 h bioavailability (h) (ng/ml) (ng ·h/ml) (%) Glucophage 3.5 1280 10 500 100 Microcapsules 7.1 1015   9660 92 of example 2

The microcapsules of the invention thus represent a significant overhangin the field of the administration of metformin by the oral route forthe treatment of diabetes.

1. A medicament based on at least one biguanide anti-hyperglycemic agent which is administered by the oral route, wherein the medicament comprises a plurality of microcapsules for oral administration; wherein the microcapsules have a particle size between 50 and 750 microns; wherein the microcapsules have a core comprising at least one biguanide antihyperglycemic agent; wherein the mean fraction by mass of the biguanide in the microcapsules is greater than 50%; wherein the microcapsules are coated with a coating film adapted to prolong the release in vivo of the biguanide antihyperglycemic agent and to extend over at least 8 hours the dissolution of the biguanide antihyperglycemic agent in an in vitro dissolution test; wherein the coating film comprises at least one film-forming macromolecule and at least one plasticizer; wherein the film forming macromolecules are selected from the group consisting of: cellulose ethers, cellulose ethers/esters, cellulose esters, cellulose diesters, cellulose triesters, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate and triacetate, cellulose acetate/propionate, cellulose acetate/butyrate, polymethacrylates, waxes, vinyl acetate copolymers, and mixtures thereof; wherein the plasticizers are selected from the group consisting of: tributyl acetylcitrate, triethyl acetylcitrate, acetylated glycerides, castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate, dibutyl sebacate, dimethyl phthalate, glycerol, glycerol monostearate, glyceryl triacetate, polyethylene glycol, polyoxyethylene/polyoxypropylene copolymers, propylene glycol, tributyl citrate, triethyl citrate, adipate, azelate, enzoate, citrate, citric acid esters, vegetable oils, glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, glycerol tributyrate, and mixtures thereof; wherein the coating film is not an enteric composition; and wherein the coating film does not have a nitrogenous polymer, present in a proportion of 2 to 25%, by weight on a dry basis with respect to the total mass of the coating composition and composed of at least one polyacrylamide, and/or one poly-N-vinylamide and/or one poly-N-vinyllactam.
 2. The medicament according to claim 1, wherein the size and the coating of the microcapsules are chosen so that the medicament's bioavailability during oral administration on a full stomach is at least equal to its bioavailability during oral administration on an empty stomach.
 3. The medicament according to claim 1, wherein the antihyperglycemic is a biguanide selected from the group consisting of: metformin, buformin, metformin salts, and buformin salts.
 4. The medicament according to claim 1, wherein the dissolution of the biguanide antihyperglycemic agent extends over at least 8 hours, in an in vitro dissolution test known as the type II dissolutest in accordance with the Pharmacopoeia.
 5. The medicament according to claim 1, wherein the form of the medicament is selected from the group consisting of: a tablet which can disintegrate in the mouth, a tablet which can disintegrate in a liquid, a powder, a suspension and a gelatin capsule.
 6. The medicament according to claim 1, wherein the total dose of biguanide antihyperglycemic agent in the medicament is between 800 and 1200 mg.
 7. The medicament according to claim 1, wherein the medicament comprises at least one thousand of the microcapsules.
 8. The medicament according to claim 1, wherein the core of the microcapsules is a granule comprising said biguanide antihyperglycemic agent and granulation excipients.
 9. The medicament according to claim 8 wherein the core of the microcapsules is a monocrystal of biguanide antihyperglycemic agent.
 10. The medicament according to claim 1 wherein the coating film comprises one or more products selected from the group consisting of: soluble fillers, insoluble fillers, lubricants, dyes, pigments, and mixtures thereof.
 11. The medicament according to claim 1, wherein the film-forming macromolecules are selected from the group consisting of ethylcellulose, ammonio methacrylate copolymer Type B, ammonio methacrylate copolymer Type A, cellulose acetate, and mixtures thereof.
 12. The medicament according to claim 1, wherein the film-forming macromolecules comprise-cellulose derivatives and at least one pharmaceutically acceptable hydrophilic polymer.
 13. The medicament according to claim 12, wherein the fraction by mass of cellulose derivatives is between 30 and 90%.
 14. A method for the preparation of the medicament of claim 1, wherein the method consists of: creating granules comprising biguanide antihyperglycemic agent; and then spraying, over these granules a coating solution comprising film-forming macromolecules and plasticizers, wherein the coating film is not an enteric composition; and wherein the coating film does not have a nitrogenous polymer, present in a proportion of 2 to 25%, by weight on a dry basis with respect to the total mass of the coating composition and composed of at least one polyacrylamide, and/or one poly-N-vinylamide and/or one poly-N-vinyllactam; such that the resulting microparticle is 50 to 1000 microns in diameter.
 15. The method according to claim 14, wherein the coating solution comprises other excipients selected from the group consisting of: soluble fillers insoluble fillers, lubricants, dyes, pigments, and mixtures thereof.
 16. A method for administering an orally administered medicament based on at least one biguanide anti-hyperglycemic agent which can be easily swallowed and which contributes to the control of glycemia over at least 12 h in a reliable manner and while limiting problems of bypass, of accumulation and of localized and massive release of biguanide anti-hyperglycemic agent, said method consisting in using a plurality of microcapsules; wherein each microcapsule is composed of a core comprising at least one antihyperglycemic; wherein a coating film comprising at least one film-forming macromolecule and at least one plasticizer is applied to the core to prolong the release in vivo of the antihyperglycemic agent, wherein the coating film is adapted to prolong the release in vivo of the biguanide antihyperglycemic agent and to extend over at least 8 hours the dissolution of the biguanide antihyperglycemic agent in an in vitro dissolution test; wherein the final particle size of the microcapsule is between 50 and 750 microns; wherein the mean fraction by mass of the biguanide in the microcapsules is greater than 50%; wherein the film forming macromolecules are selected from the group consisting of: cellulose ethers, cellulose ethers/esters, cellulose esters, cellulose diesters, cellulose triesters, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate and triacetate, cellulose acetate/propionate, cellulose acetate/butyrate, polymethacrylates, waxes, vinyl acetate copolymers, and mixtures thereof; wherein the plasticizers are selected from the group consisting of: tributyl acetylcitrate, triethyl acetylcitrate, acetylated glycerides, castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate, dibutyl sebacate, dimethyl phthalate, glycerol, glycerol monostearate, glyceryl triacetate, polyethylene glycol, polyoxyethylene/polyoxypropylene copolymers, propylene glycol, tributyl citrate, triethyl citrate, adipate, azelate, enzoate, citrate, citric acid esters, vegetable oils, glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, glycerol tributyrate, and mixtures thereof; wherein the coating film is not an enteric composition; wherein the coating film does not have a nitrogenous polymer, present in a proportion of 2 to 25%, by weight on a dry basis with respect to the total mass of the coating composition and composed of at least one polyacrylamide, and/or one poly-N-vinylamide and/or one poly-N-vinyllactam; and wherein when the medicament is administered, the blood glycemia over at least 12 hour is controlled while decreasing the problems of bypass, accumulation and localized and massive release of biguanide anti-hyperglycemic agent.
 17. A method for the treatment of type II diabetes, in which the method comprises administering to a patient with type II diabetes therapeutic amount of the medicament of claim
 16. 18. A method for the treatment of type II diabetes, in which the method comprises administering to a patient with type II diabetes a therapeutic amount of the medicament of claim
 14. 